Nitric oxide: what's new to NO?

Abstract

Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease.

Keywords: CD47; NOS; cardiac; cardiovascular; cytochrome b5 reductase 3; matricellular; nitric oxide; signal transduction; thrombospondin-1.

Fig. 1.

Recent findings provide for additional levels of nitric oxide (NO) regulation. Receptor-mediated signaling such as vascular endothelial growth factor receptor 2 (VEGFR2) and acetylcholine (ACh) as well as protein partners including heat shock protein 90 (HSP90), calmodulin (CaM), and caveolin-1 (Cav-1) regulate endothelial NO synthase (eNOS) activity and thus NO production in the vascular wall. Once generated, NO diffuses from endothelium to various cell types including vascular smooth muscle cells, platelets, and monocytes where it activates its receptor soluble guanylate cyclase (sGC), increases production of cyclic guanosine monophosphate (cGMP), and controls cell function. In addition to paracrine processes, NO controls or alters intracellular functions such as mitochondria biogenesis, telomerase activity, reactive oxygen species (ROS) production, and low-density lipoprotein (LDL)-oxidation. Heme scavenging proteins, such as hemoglobin-α, are expressed in endothelial cells (EC) and serve as a “buffer” to control NO diffusion, a process that is regulated at endothelial (MEJ)-smooth muscle cell junctions by cytochrome b5 reductase 3 (Cb5r3). Extracellular “outside-in” signals, such as thrombospondin-1 (TSP1)-cluster of differentiation 47 (CD47) also have the ability to limit on NO signaling through inhibition of eNOS, sGC, and cGMP-dependent protein kinase (PKG) activity. EPC, endothelial progenitor cells; MR3, muscarinic receptor 3; MEJ, myo-endothelial junction; SMC, smooth muscle cell; GPCR, G protein-coupled receptor. [Printed with permission from Anita Impagliazzo.]